Multiscale Modeling of Dynamin Induced Membrane Fission The major pathway for recycling the cellular machinery involved in neurotransmission back into the neuron is clathrin mediated endocytosis (CME). The final stage of endocytosis involves the recruitment of the protein dynamin to the neck of the vesicle to cut the membrane and release the vesicle to the interior of the cell. Dynamin forms a helical protein coat around the vesicle neck that ultimately disrupts the lipid membrane and the vesicle is released. Dynamin is able to causes membrane scission by undergoing a large conformational change after catalyzing the hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Two mechanisms for dynamin induced membrane fission have been proposed. In the constriction model, the explanation is that hydrolysis leads to constriction or twisting of the helical coat, which destabilizes the inner layer of the membrane. In the disassembly model, hydrolysis leads to disassembly of the helical coat, which causes destabilization of the membrane neck and results in fission. In both of these mechanisms, a super-constricted membrane state is achieved prior to membrane scission. Distinguishing between these two models, requires two key major points to be understood: 1) how is the energy released from GTP hydrolysis used by dynamin and 2) how is the super-constricted membrane state reached? We are proposing that an innovative multiscale molecular-modeling approach would be able to compare the two mechanisms directly using computer simulation and determine which is the most energetically favorable. The major innovation in this method is that it maintains the underlying physics and chemistry by combining smaller scale atom-level molecular dynamics simulations with larger scale, low resolution coarse-grained simulations in an iterative way. The overall goal of this work is to develop a multiscale model of dynamin that can be used to determine whether dynamin induced membrane scission occurs via a constriction or protein coat disassembly mechanism. To determine the membrane fission mechanism, we need to determine how the energy released by GTP hydrolysis leads to changes in the structure of dynamin and how dynamin interacts with the membrane. This information can then be combined with simulations of the dynamin protein in solution to develop a model that can be used to directly simulate the fission process. This will help us determine the actual mechanism of membrane scission.